Facile Knoevenagel and domino Knoevenagel/Michael reactions using gel-entrapped base catalysts

Article abstract of DOI:10.1002/hlca.201100133

An efficient method for Knoevenagel condensation of arenecarbaldehydes with active methylene compounds such as barbituric acid and Meldrum's acid in the presence of gel-entrapped base catalysts is reported. The method has been extended to the one-pot synthesis of arylmethylene-bis[3-hydroxycyclohex-2-en-1- one] derivatives from dimedone (=5,5-dimethylcyclohexane-1,3-dione) and arenecarbaldehydes by using domino Knoevenagel/Michael reaction sequence. Copyright

Full text of DOI:10.1002/hlca.201100133

Helvetica Chimica Acta – Vol. 94 (2011)
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Facile Knoevenagel and Domino Knoevenagel/Michael Reactions Using Gel-
Entrapped Base Catalysts
by Shital Shinde, Gajanan Rashinkar, Arjun Kumbhar, Santosh Kamble, and Rajashri Salunkhe*
Department of Chemistry, Shivaji University, Kolhapur, 416004, M.S., India
(phone: þ 912312609169; fax: þ 912312692333; e-mail: rss234@rediffmail.com)
An efficient method for Knoevenagel condensation of arenecarbaldehydes with active methylene
compounds such as barbituric acid and Meldrumꢀs acid in the presence of gel-entrapped base catalysts is
reported. The method has been extended to the one-pot synthesis of arylmethylene-bis[3-hydroxycy-
clohex-2-en-1-one] derivatives from dimedone (¼ 5,5-dimethylcyclohexane-1,3-dione) and arenecarbal-
dehydes by using domino Knoevenagel/Michael reaction sequence.
Introduction. – Knoevenagel condensation is one of the most common and versatile
reaction that is used for C,C bond formation. This reaction has been widely used for the
preparation of several intermediates which are useful in perfumes, cosmetics, and
bioactive compounds [1][2]. The products of Knoevenagel condensation also have
widespread applications including inhibition of antiphosphorylation of EGF receptor
and antiproliferative activity [3]. Due to their importance from a pharmacological,
industrial, and synthetic point of view, several methods for the Knoevenagel
condensation have been reported. These methods include both homogeneous as well
as heterogeneous conditions, catalyzed by bases such as piperidine [4], ethylenedi-
amines or their corresponding ammonium salts, 4-(dimethylamino)pyridine (DMAP),
or organocatalyst such as glycine, l-proline, and alanine [5]. In recent years, resins [6],
montmorilloniteꢀKSF [7], ZrCl4ꢀSiO2 [8], ionic liquids [9], microwave irradiation [10]
and Lewis acids [11] have also been employed. Although the literature on Knoevenagel
condensation contains a rich array of versatile methodologies, new approaches remain
valuable additions to the contemporary arsenal of synthetic strategies.
The concept of Gel-Entrapped Base Catalysts (GEBCs) combines the advantages
of alkali and organic bases with those of heterogeneous supports [12]. These catalysts
are prepared by immobilization of alkali or organic bases by entrapping them in an
aqueous gel matrix of agarꢀagar which is a polymer composed of repeating agarobiose
units alternating between 3-linked b-d-galactopyranosyl (G) and 4-linked 3,6-anhydro-
a-l-galactopyranosyl (LA) units as shown in Fig. 1. This method reduces the amount of
bases used, and allows easy and efficient separation of products from the catalyst.
Besides this, bases like alkalis, when exposed to air, absorb moisture and are spoiled.
On the contrary, the GEBCs do not absorb moisture on exposure to air and remain
intact. The use of GEBCs in organic synthesis also provides an excellent opportunity of
recyclability and reusability, which is seldom possible using bases alone as catalysts.
ꢁ 2011 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Helvetica Chimica Acta – Vol. 94 (2011)
Fig. 1. Stucture of agarose
However, despite their well recognized advantages, there have been only limited and
sporadic reports dealing with use of GEBCs in synthetic chemistry [13][14]. The
interesting properties of GEBCs spurred us to probe their barely exploited potential in
organic synthesis.
In our continuing search for novel catalysts in organic synthesis [15], we report
herein the Knoevenagel condensation of arenecarbaldehydes with active methylene
compounds like barbituric acid (¼ pyrimidine-2,4,6(1H,3H,5H)-trione) and Meldrumꢀs
acid (¼2,2-dimethyl-1,3-dioxane-4,6-dione) and one-pot synthesis of arylmethylene-
bis[3-hydroxycyclohex-2-ene-1-one] derivatives from dimedone and arenecarbalde-
hydes by using domino Knoevenagel/Michael reaction sequence in the presence of
GEBCs.
Results and Discussion. – Initially, we focused our attention in the synthesis of
various GEBCs. Morpholine, piperidine, and KOH were selected as bases for the
synthesis of GEBCs. A series of experiments were conducted in which different
concentrations of selected bases (5 – 25%) were dissolved in a varying amount of
agarꢀagar in H2O. Finally, we found that 20% (w/w) of agarꢀagar/aqua gel containing
10% bases resulted in the formation of soft gels that served as GEBCs in the present
work. All the GEBCs were light-yellow jelly-like substances that could be cut into
pieces (Fig. 2).
Fig. 2. Photograph of KOH-GEBC

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Thermal behavior of GEBCs was studied by thermogravimetric analysis (TGA)
and differential scanning calorimetry (DSC; Fig. 3). The TGA/DSC curves of KOH-
GEBC (Fig. 3, a) revealed that degradation of gel occured with increase in temperature
and was completed at 1518 as evident from strong endothermic peak observed in DSC.
The thermal decomposition of agar polymer started around 2408 and was very slow up
to 4758, indicating that the polymer matrix might have undergone some structural
changes (which were slightly exothermic) leading to complete exothermic decom-
position of polymer material around 5008, leaving only anhydrous KOH which
decomposed above 8008. However, in the case of GEBCs containing morpholine and
piperidine (Fig. 3,b and c), the decomposition of bases was observed before the
degradation of polymer. The process of base degradation was slow due to intercalation
of morpholine and piperidine in polymer matrix.
Our next task was to demonstrate the catalytic activity of GEBCs in the
Knoevenagel condensation. As a trial case, equimolar mixture of barbituric acid and
benzaldehyde (5 mmol each) was stirred in the presence of 1 g of various GEBCs in
EtOH at ambient temperature until the completion of reaction as monitored by TLC.
The results are compiled in Table 1. Among the various GEBCs, KOH-GEBC was
found to be better than piperidine- and morpholine-GEBCs. The stupendous increase
in the yield of product as well as reaction times of KOH-GEBC may be attributed to
higher basicity of KOH as compared to piperidine and morpholine. Further, we have
also studied the effect of solvents on a model reaction using KOH-GEBC. We observed
that, in solvents such as EtOH, i-PrOH, MeOH, CH2Cl2, and toluene, the yields of the
products were considerably higher in EtOH than in others (Table 2). It is worthy noting
that, in a blank experiment, no reaction was observed under similar conditions in the
absence of GEBC. The striking feature of all the reactions was the isolation of products.
It was interesting to observe that, after a specified time, the product precipitated out of
the mixture that could be isolated simply by filtration. The product obtained after
sufficient washing with H2O was found to be practically pure.
Table 1. Screening of Various GEBCs for Knoevenagel Condensationa)
Entry
GEBC
Time [min]
Yieldb) [%]
1
2
3
KOH-GEBC
Morpholine-GEBC
Piperidine-GEBC
10
10
10
92
65
70
a) The reaction of benzaldehyde with barbituric acid. b) Yields of isolated products.
Table 2. Solvent Effect on the Knoevenagel Condensation Using KOH-GEBCa)
Entry
Solvent
Time [min]
Yieldb) [%]
1
2
3
4
5
EtOH
15
15
15
15
15
92
70
60
55
50
i-PrOH
MeOH
CH2Cl2
Toluene
a) The reaction of benzaldehyde with barbituric acid. b) Yields of isolated products.

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Helvetica Chimica Acta – Vol. 94 (2011)
Fig. 3. DSC-TGA graph of a) KOH-GEBC, b) Morpholine-GEBC, and c) Piperidine-GEBC

Helvetica Chimica Acta – Vol. 94 (2011)
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Because excellent results were obtained with KOH-GEBC, we employed this
particular catalyst for further studies. To investigate the feasibility of KOH-GEBC, a
number of structurally diverse arenecarbaldehydes were reacted with barbituric acid
(1) in EtOH. The results of the reactions are collected in Table 3. In all cases,
arylmethylidene-barbituric acids were the sole products, and no anomalies were noted.
With both electron-poor and electron-rich benzaldehydes, the corresponding products
were obtained in good-to-excellent yields. The reaction of the sterically hindered 2-
substitued benzaldehydes gave even higher yields, highlighting the general applicability
of the protocol. The identity of all the compounds was ascertained on the basis of IR,
1H- and 13C-NMR, and MS data. The physical and spectroscopic data are in agreement
with the proposed structures.
Table 3. KOH-GEBC-Catalyzed Knoevenagel Condensation of Arenecarbaldehydes with Barbituric
Acida)
Entry Ar
Aldehyde Product Time [min] Yieldb) [%] M.p. [8]c)
1
2
3
4
5
6
7
8
9
Ph
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
3f
3g
3h
3i
10
10
8
10
10
10
10
10
10
92
89
79
80
86
76
91
81
81
271 (273 [16])
265 (263 [16])
280 (281 [16])
252 (253 [17][18])
297 (299 [19])
290 (291 [19])
276 (277 [17][18])
300 (298 [19])
273 (27 [20])
4-(Me2N)ꢀC6H4
4-ClꢀC6H4
2-ClꢀC6H4
4-OHꢀC6H4
3-MeO,4-OHꢀC6H3 2f
4-MeOꢀC6H4
4-MeꢀC6H4
2g
2h
2i
Thiophen-2-yl
a) All products were characterized by IR, 1H- and 13C-NMR, and MS analyses. b) Yields of isolated
products. c) Literature values in parentheses.
To investigate the scope and limitations of the method, we applied similar
conditions to Knoevenagel condensation of arenecarbaldehydes with other active
methylene compound like Meldrumꢀs acid (4). We found that the reactions proceeded
equally well forming the corresponding products in excellent yields within shorter
duration reflecting the versatility of the method (Table 4).
Arylmethylene-bis[3-hydroxycyclohex-2-en-1-one] derivatives constitutes impor-
tant class of scaffolds that are widely used for the syntheses of xanthenes and
acridinediones [24]. In addition, they have also shown potent activities as antioxidants,
lipoxygenase inhibitors [25], and a new clinical class of tyrosinase inhibitors against
crucial dermatological disorders like hyperpigmentation skin melanoma [26]. Al-
though a large number of synthetic protocols have been developed for arylmethylene-
bis[3-hydroxycyclohex-2-en-1-one] derivatives using cyclic 1,3-dicarbonyl compounds
and arenecarbaldehydes, in which the domino Knoevenagel/Michael addition reactions

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Helvetica Chimica Acta – Vol. 94 (2011)
Table 4. KOH-GEBC-Catalyzed Knoevenagel Condensation of Arenecarbaldehydes with Meldrumꢀs
Acida)
Entry Ar
Aldehyde Product Time [min] Yieldb) [%] M.p. [8]c)
1
2
3
4
5
6
7
8
Ph
2a
2b
2c
2d
2e
5a
5b
5c
5d
5e
5f
5g
5h
10
10
10
10
10
10
10
10
88
89
76
87
78
77
75
80
84 (85 [21 – 23])
173 (174 [21 – 23])
163 (162 [21 – 23])
135 (133 [21 – 23])
198 (197 [21 – 23])
128 (129 [23])
4-(Me2N)ꢀC6H4
4-ClꢀC6H4
2-ClꢀC6H4
4-OHꢀC6H4
3-MeO,4-OHꢀC6H3 2f
4-MeOꢀC6H4
2g
2h
127 (126 [23])
158 (159 [23])
4-MeꢀC6H4
a) All products were characterized by IR, 1H- and 13C-NMR, and MS analyses. b) Yields of isolated
products. c) Literature values in parenthesis.
are key steps [27], there is still a scope for improvement especially towards developing
an efficient method using highly reusable catalyst. This prompted us to investigate the
synthesis using KOH-GEBC. Accordingly, the reactions of dimedone (¼ 5,5-dimethyl-
cyclohexane-1,3-dione; 6; 1 mmol) with variety of arenecarbaldehydes (2 mmol) were
examined in EtOH in the presence of KOH-GEBC at ambient temperature. As shown
in Table 5, all the arenecarbaldehydes reacted readily with 6 to afford corresponding
arylmethylene-bis[3-hydroxycyclohex-2-en-1-one] derivatives in 65 – 95% yields in a
very short reaction time.
In the GEBCs, the reagent entrapped in the gel may leach into the solvent. To study
the leaching of KOH in solvent, 1 g of KOH-GEBC was stirred in 5 ml of EtOH at
room temperature. The KOH-GEBC was filtered, and H2O (3 ml) was added to the
filtrate. The KOH leached out was then determined by titrating against 0.1n succinic
acid solution using phenolphthalein as an indicator. It was observed that only 1.5%
KOH leached out from gel into EtOH. Using the same amount of KOH as that leached
out, the reaction between barbituric acid (1)/Meldrumꢀs acid (4) and benzaldehyde (2a)
did not give quantitative yield of the corresponding product. This clearly demonstrated
that catalysis was solely due to intact KOH-GEBC rather than leached KOH.
The recovery and reuse of catalysts is highly preferable for the large-scale
operations and from the industrial point of view. To check the possibility of GEBC
recycling, the reaction of barbituric acid (1), Meldrumꢀs acid (4), and dimedone (6)
with benzaldehyde (2a) using KOH-GEBC in EtOH was studied. After completion of
the reaction, the KOH-GEBC was separated from mixture, washed with EtOH, and
reused in another reaction with identical substrates. The catalyst showed a remarkable
recyclability, as the yield of the product decreased only slightly from the first run to the
fifth run (Fig. 4).

Helvetica Chimica Acta – Vol. 94 (2011)
1949
Table 5. KOH-GEBC-Catalyzed Domino Knoevenagel/Michael Reaction Sequence of Arenecarbalde-
hydes with Dimedonea)
Entry Ar
Aldehyde Product Time [min] Yieldb) [%] M.p. [8]c)
1
2
3
4
5
6
7
8
Ph
2a
2b
2c
2d
2e
7a
7b
7c
7d
7e
7f
7g
7h
10
10
10
10
10
10
10
10
84
87
89
81
85
87
88
83
196 (192 – 194 [28])
188 (186 – 188 [28])
140 (140 – 142 [28])
235 (238 – 240 [29])
200 (202 – 205 [28])
122 (122 – 124 [30])
145 (146 – 148 [28])
129 (128 – 130 [28])
4-(Me2N)ꢀC6H4
4-ClꢀC6H4
2-ClꢀC6H4
4-OHꢀC6H4
3-MeO,4-OHꢀC6H3 2f
4-MeOꢀC6H4
4-MeꢀC6H4
2g
2h
a) All products were characterized by IR, 1H- and 13C-NMR, and MS analyses. b) Yields of isolated
products. c) Literature values in parenthesis.
Fig. 4. Recyclability of KOH-GEBC
Conclusions. – In conclusion, a novel and highly efficient methodology for
Knoevenagel condensation of arenecarbaldehydes with active methylene compounds
has been developed using recyclable GEBC. The protocol has been successfully applied
for the one-pot synthesis of arylmethylene-bis[3-hydroxycyclohex-2-en-1-one] deriv-
atives from dimedone and arenecarbaldehydes by using domino Knoevenagel/Michael
reaction sequence. The method offers several significant advantages, such as high

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Helvetica Chimica Acta – Vol. 94 (2011)
conversions, easy handling, clean reaction profile, and short reaction time, which render
it a useful and an attractive addition to the existing methodologies for the synthesis of
Knoevenagel condensation products.
Experimental Part
General. All chemicals were obtained from local suppliers and used without further purification.
1
M.p.: Open capillary; uncorrected. IR Spectra: Perkin-Elmer FT-IR spectrometer; KBr discs. H- and
13C-NMR spectra: Bruker Avon 300 MHz spectrometer with DMSO or CDCl3 as solvent, and TMS as
internal reference. MS: Shimadzu QP2010 GC/MS with an ion source temp. of 2808. Thermal gravimetric
analysis (TGA): instrument STA 1500 in the presence of static air at a linear heating rate of 108/min from
258 to 10008.
Preparation of GEBCs. To a boiling mixture of agarꢀagar (20 ml) in H2O (60 ml) was added a
mixture of base (10 g) in H2O (10 ml). The resultant soln. was boiled with stirring for 5 min and cooled in
ice bath to yield the desired GEBC.
General Procedure for Knoevenagel Condensation of Arenecarbaldehydes with Active Methylene
Compounds. A mixture of arenecarbaldehyde (5 mmol) and active methylene compound (5 mmol) was
stirred in the presence of GEBC (1 g) in 5 ml of EtOH at ambient temp. until the completion of the
reaction as monitored by TLC. The resulting crude product was filtered off, washed with H2O and
recrystallized from EtOH to afford pure products.
General Procedure for the Synthesis of Arylmethylene-bis(3-hydroxycyclohex-2-en-1-one) Deriva-
tives. A mixture of arenecarbaldehyde (5 mmol) and active methylene compound (10 mmol) was stirred
in the presence of GEBC (1 g) in 5 ml of EtOH until the completion of the reaction as monitored by
TLC. The resulting crude product was purified by recrystallization.
Data
of
Representative
Compounds.
5-[4-(Dimethylamino)benzylidene]pyrimidine-
2,4,6(1H,3H,5H)-trione (3b). IR (KBr): 3196, 3073, 1715, 1649, 1611, 1505. 1H-NMR (300 MHz,
DMSO): 3.11 (s, 6 H); 6.69 (s, 1 H); 8.37 – 8.01 (m, 4 H); 10.80 (s, 1 H); 10.92 (s, 1 H). 13C-NMR
(75 MHz, DMSO): 40.0; 110.1; 111.6; 120.6; 139.5; 150.7; 154.2; 156.4; 162.9; 165.1. EI-MS: 259 (Mþ).
5-(4-Methoxybenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (3g). IR (KBr): 3070, 1727, 1675,
1602, 1547, 1215. 1H-NMR (300 MHz, DMSO): 3.84 (s, 1 H); 6.91 (s, 1 H); 7.73 – 8.31 (m, 4 H); 10.98 (s,
1 H); 11.09 (s, 1 H). 13C-NMR (75 MHz, DMSO): 55.4; 113.9; 114.4; 127.7; 137.9; 150.4; 156.5; 162.3;
164.0; 164.2. EI-MS: 246 (Mþ).
5-[4-(Dimethylamino)benzylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (5b). IR (KBr): 3090, 2980,
1
2921, 2850, 1720, 1698, 1610, 1399, 1262, 819. H-NMR (300 MHz, CDCl3): 1.65 (s, 6 H); 3.10 (s, 6 H);
6.67 (d, J ¼ 9, 2 H); 8.11 (d, J ¼ 9, 2 H); 8.15 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 27.2; 40.0; 103.2;
104.5; 111.3; 119.7; 138.9; 154.7; 157.4; 161.2; 164.7. EI-MS: 275 (Mþ).
5-(4-Methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (5g). IR (KBr): 3075, 2997, 2950,
2900, 1740, 1714, 1575, 1390, 1284, 837. 1H-NMR (300 MHz, CDCl3): 1.80 (s, 6 H); 3.92 (s, 3 H); 7.01 (d,
J ¼ 9, 2 H); 8.24 (d, J ¼ 9, 2 H); 8.27 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 27.5; 55.5; 103.9; 111.0; 114.3;
124.8; 137.6; 157.7; 160.1; 163.7; 164.5. EI-MS: 262 (Mþ).
2-[(2-Hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)(phenyl)methyl]-5,5-dimethylcyclohexane-1,3-
dione (7a). IR (KBr): 2962, 1594, 1447, 1374, 1299, 1249, 1165, 843. 1H-NMR (300 MHz, CDCl3): 1.11 (s,
6 H); 1.24 (s, 6 H); 2.28 (d, 4 H), 2.50 (d, J ¼ 16.2, 8 H); 5.55 (s, 1 H); 7.09 – 7.30 (m, 5 H); 11.92 (s, 1 H).
13C-NMR (75 MHz, CDCl3): 25.3; 27.7; 29.3; 29.8; 38.7; 44.4; 110.6; 113.9; 123.5; 125.4; 146.7; 188.2;
164.7. EI-MS: 367 (Mþ).
2-{[4-(Dimethylamino)phenyl](2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)methyl}-5,5-dime-
thylcyclohexane-1,3-dione (7b). IR (KBr): 2959, 1660, 1600, 1369, 1306, 1230, 1164, 1064, 910, 812.
1H-NMR (300 MHz, CDCl3): 1.10 (s, 6 H); 1.23 (s, 6 H); 2.33 (d, 4 H), 2.42 (d, J ¼ 16.1, 8 H); 2.90 (s,
6 H); 5.47 (s, 1 H); 6.65 – 7.26 (m, 4 H); 11.95 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 27.3; 29.7; 31.3; 31.8;
40.7; 46.4; 47.0; 112.6; 115.9; 125.5; 127.4; 148.7; 189.0; 190.2. EI-MS: 410 (Mþ).

Helvetica Chimica Acta – Vol. 94 (2011)
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We gratefully acknowledge the financial support from the Department of Science Technology and
University Grants Commission for FIST and SAP, respectively.
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Received March 31, 2011